Abivertinib synergistically strengthens the anti‐leukemia activity of venetoclax in acute myeloid leukemia in a BTK‐dependent manner

Abstract

B-cell lymphoma 2 (BCL-2), a crucial member of the anti-apoptotic BCL-2 family, is frequently dysregulated in cancer and plays an important role in acute myeloid leukemia (AML). Venetoclax is a highly selective BCL-2 inhibitor that has been approved by the FDA for treating elderly AML patients. However, the emergence of resistance after long-term treatment emphasizes the need for a deeper understanding of the potential mechanisms of resistance and effective rescue methods. By using RNA-seq analysis in two human AML cohorts made up of three patients with complete remission and three patients without remission after venetoclax treatment, we identified that upregulation of BTK enabled AML blast resistance to venetoclax. Interestingly, we found that abivertinib, an oral BTK inhibitor, could synergize with venetoclax to inhibit the proliferation of primary AML cells and cell lines. It is worth noting that the combination of the two effectively enhanced the sensitivity of two AML patients (AML#3 and AML#12) to venetoclax. In this study, we demonstrated that combined use of the two drugs can synergistically inhibit the colony-forming capacity of AML cells, arrest the AML cell cycle in the G0/G1 phase, and inhibit the BCL-2 anti-apoptotic family protein, activating the caspase family to induce apoptosis. Mechanistically, knockdown of BTK in AML cell lines impaired the synergistic effect of the two drugs. In vivo study showed similar results as those seen in vitro. Abivertinib in combination with venetoclax could significantly prolong the survival time and reduce the tumor burden of MV4-11-NSG mice compared with those of control and single-agent groups. Our in vitro and in vivo studies have shown that the combination of abivertinib and venetoclax may benefit AML patients, especially in patients resistant to venetoclax or those that relapse. New clinical trials will be planned.

Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials

“…Avitinib is also a novel BTK inhibitor. 161,162 Oritinib (SH-1028) ( 56) is an irreversible, selective thirdgeneration EGFR TKI. Oritinib overcomes T790M-mediated drug resistance in NSCLC and inhibits WT-EGFR, EGFR L858R , EGFR L861Q , EGFR L858R/T790M , EGFR d746-750 , and EGFR d746-750/T790M kinases.…”

Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis

“…When used as a single agent, ibrutinib, a Btk inhibitor, is associated with increased incidence of thrombocytopenia [15]. Previous studies demonstrate that abivertinib has promising activity against mantle cell lymphoma (MCL), diffuse large B cell lymphoma, and acute myeloid leukemia (AML) by inhibiting Btk activity [16][17][18][19]. An ongoing phase I trial (NCT03060850) shows that abivertinib is safe and tolerable with clinical efficacy in patients with relapsed or refractory B cell malignancies [20].…”